Final Report Summary - FUNCCOMI (FUNCTIONAL CONNECTIVITY IN CORTICAL MICROCIRCUITS)
My research focused on the inhibitory circuitry that regulates processing of visual information in the cortex. By using a variety of optical tools, I’ve studied the role of a class of inhibitory interneurons, the vasoactive intestinal peptide positive (VIP+) interneurons, in modulating visual-evoked responses of cortical neurons.
The results of this study yielded three papers as first author. In the first paper (‘Cortical control of spatial resolution by VIP+ interneurons’, In press; see attached document), we utilized in vivo two-photon Ca2+ imaging combined with bidirectional optogenetic manipulations (activation and suppression), and discovered that VIP+ interneurons play a causal role in regulating the spatial frequency (SF) tuning of neurons in mouse visual cortex. These findings establish the inhibitory circuitry that regulates modulations of SF in the cortex, which is a hallmark of visual attention. This paper will be of interest to a wide community of scientists due to the combination of optical techniques and the clarity of the results, and most importantly, it opens the door to understanding the mechanisms by which the cortex realizes visual attention. Therefore, in the long run it has the potential to impact Visual Attention Therapy, which currently helps brain injury and stroke survivors to improve scanning abilities, and people with visual neglect to improve awareness of the neglected side of space.
In the second paper (‘VIP+ interneurons control neocortical activity across brain states’) we used chemogenetic agents to demonstrate that VIP+ interneurons have a causal role in the generation of high-activity regimes during spontaneous and stimulus-evoked neocortical activity. These findings are at the heart of an ongoing scientific debate regarding the role of this important class of interneurons, and it shows they are active not only during locomotion (as previously shown) but also during awake immobility, under light anesthesia, or in response to visual stimulation, and their suppression shifts the network to a low-activity regime. This paper is of broad interest as it lies at the heart of the discussion regarding the mechanisms by which neuromodulation is shaping sensory-evoked responses in the cortex.
In the third paper (‘Orientation tuning depends on spatial frequency in mouse visual cortex’), we investigated basic aspects of visual encoding and discovered that the orientation selectivity of neurons in layer 2/3 of the primary visual cortex depends on the spatial frequency (SF) of the stimulus. This dependence was demonstrated quantitatively by a decrease in the selectivity strength of cells in non-optimum SF, and more importantly, it was also demonstrated qualitatively by a shift in the preferred orientation of cells in non-optimum SF. To explain this dependence, we investigated various receptive field models and showed that a spatially asymmetric Gabor-type model can account for these observations, and thus raised the question of the role of spatial asymmetry in encoding natural scenes. This study combines experimental and theoretical work and provides new insight into the fundamentals of receptive field structure of cells in the visual cortex.
We additionally investigated properties of different neocortical subpopulations of interneurons and showed in vivo and in vitro, that members of two non-overlapping populations expressing somatostatin (SOM) or VIP are active as a group rather than individually (‘Cooperative Subnetworks of Molecularly Similar Interneurons in Mouse Neocortex’). Lastly, using two-photon stimulation of single neurons we explored how VIP interneurons affect the local circuit. We found that VIP interneurons have narrow axons and inhibit nearby SOM interneurons, which themselves inhibit pyramidal cells. Moreover, via this lateral disinhibition, VIP cells make local and transient “holes” in the inhibitory blanket extended by SOM cells. Therefore, VIP interneurons, themselves regulated by neuromodulators, may enable selective patterns of activity to propagate through the cortex, by generating a “spotlight of attention”.
Collectively, in-depth investigation of this population of cells, which included both descriptive and mechanistic inquiries, revealed a critical role of disinhibition in neural circuit computation that facilitates attentional mechanisms in the cortex.
(For further information on the methods used for these studies, please visit http://www.columbia.edu/cu/biology/faculty/yuste/index.html
https://www.youtube.com/watch?v=eP92qEDZ6rE)
The results of this study yielded three papers as first author. In the first paper (‘Cortical control of spatial resolution by VIP+ interneurons’, In press; see attached document), we utilized in vivo two-photon Ca2+ imaging combined with bidirectional optogenetic manipulations (activation and suppression), and discovered that VIP+ interneurons play a causal role in regulating the spatial frequency (SF) tuning of neurons in mouse visual cortex. These findings establish the inhibitory circuitry that regulates modulations of SF in the cortex, which is a hallmark of visual attention. This paper will be of interest to a wide community of scientists due to the combination of optical techniques and the clarity of the results, and most importantly, it opens the door to understanding the mechanisms by which the cortex realizes visual attention. Therefore, in the long run it has the potential to impact Visual Attention Therapy, which currently helps brain injury and stroke survivors to improve scanning abilities, and people with visual neglect to improve awareness of the neglected side of space.
In the second paper (‘VIP+ interneurons control neocortical activity across brain states’) we used chemogenetic agents to demonstrate that VIP+ interneurons have a causal role in the generation of high-activity regimes during spontaneous and stimulus-evoked neocortical activity. These findings are at the heart of an ongoing scientific debate regarding the role of this important class of interneurons, and it shows they are active not only during locomotion (as previously shown) but also during awake immobility, under light anesthesia, or in response to visual stimulation, and their suppression shifts the network to a low-activity regime. This paper is of broad interest as it lies at the heart of the discussion regarding the mechanisms by which neuromodulation is shaping sensory-evoked responses in the cortex.
In the third paper (‘Orientation tuning depends on spatial frequency in mouse visual cortex’), we investigated basic aspects of visual encoding and discovered that the orientation selectivity of neurons in layer 2/3 of the primary visual cortex depends on the spatial frequency (SF) of the stimulus. This dependence was demonstrated quantitatively by a decrease in the selectivity strength of cells in non-optimum SF, and more importantly, it was also demonstrated qualitatively by a shift in the preferred orientation of cells in non-optimum SF. To explain this dependence, we investigated various receptive field models and showed that a spatially asymmetric Gabor-type model can account for these observations, and thus raised the question of the role of spatial asymmetry in encoding natural scenes. This study combines experimental and theoretical work and provides new insight into the fundamentals of receptive field structure of cells in the visual cortex.
We additionally investigated properties of different neocortical subpopulations of interneurons and showed in vivo and in vitro, that members of two non-overlapping populations expressing somatostatin (SOM) or VIP are active as a group rather than individually (‘Cooperative Subnetworks of Molecularly Similar Interneurons in Mouse Neocortex’). Lastly, using two-photon stimulation of single neurons we explored how VIP interneurons affect the local circuit. We found that VIP interneurons have narrow axons and inhibit nearby SOM interneurons, which themselves inhibit pyramidal cells. Moreover, via this lateral disinhibition, VIP cells make local and transient “holes” in the inhibitory blanket extended by SOM cells. Therefore, VIP interneurons, themselves regulated by neuromodulators, may enable selective patterns of activity to propagate through the cortex, by generating a “spotlight of attention”.
Collectively, in-depth investigation of this population of cells, which included both descriptive and mechanistic inquiries, revealed a critical role of disinhibition in neural circuit computation that facilitates attentional mechanisms in the cortex.
(For further information on the methods used for these studies, please visit http://www.columbia.edu/cu/biology/faculty/yuste/index.html
https://www.youtube.com/watch?v=eP92qEDZ6rE)